(1) Field of the Inventions
The invention relates to a computer system and a method for calculating ADME properties of a substance, in particular for a substance with a pharmacological effect or a substance for crop protection uses.
(2) Description of Related Art
The efficacy of active agents is determined by their interaction with the molecular biological target, as well as by the concentration at the target site. The two quantities are generally determined by different molecular parameters, and can therefore be optimized independently of one another within certain limits. While the intrinsic biochemical effect can be determined by in-vitro tests at a very early research stage for large numbers of substances, the concentration at the active site can only be studied through experiments on the whole organism (animal, plant or fungus). This means that the information can only be carried out at late research stages owing to the elaborate nature of the experiments, and is therefore unavailable for the initial optimization cycles.
In recent years, attempts have consequently been made in the pharmaceutical and crop protection industries to find alternative ways of, obtaining early information about the ADME (absorption, distribution, metabolism, excretion) behavior of active agents. Since much of the ADME behavior is influenced by easily measurable physicochemical properties, or quantities that can be calculated from the chemical structure, the procedure has since been established for experimentally determining, or calculating, such quantities with a high throughput [H. van de Waterbeemd, D. A. Smith, K. Beaumont, D. K. Walker, J. Med. Chem. 44, 1-21 (2001)].
Examples of typical properties that are conventionally taken into account for this include lipophilicity, water solubility; permeabilities across synthetic membranes or cell layers, molecular weight and numbers of particular structural features, such as hydrogen donors and acceptors. The assessment of the substances then generally involves compliance with particular limits, which are conventionally obtained from empirical values or from the statistical distribution of the properties for commercially available products [C. A. Lipinski, F. Lombardo, B. W. Dominy, P. J. Feeney, Adv. Drug Delivery Rev. 23, 3-25 (1997) and C. M. Tice, Pest Management Sci. 57, 3-16 (2001)].
A disadvantage of this method is that rigid limits are considered for individual properties that are: only indirectly relevant. The ADME properties which are actually important, however, generally depend on a plurality of these quantities simultaneously, so that the tolerable limits of the individual quantities are also dependent on their value, and absolute limit values can therefore only be set very roughly.
U.S. Pat. No. 5,901,069 discloses a computer program product for at least partially automatic calculation of molecular quantities on the basis of a substance library. This method, however, does not make it possible to calculate ADME properties.
U.S. Pat. No. 5,680,590 discloses a simulation system for the calculation of physiological data in respect of pharmacokinetic and pharmacodynamic parameters. A disadvantage of this simulation system is that the calculation does not rely directly on the basis of molecular properties of a substance to be evaluated. This model is suitable only for training purposes and does not allow calculation of the ADME properties of a new substance.
It is an object of the invention to provide an improved method for calculating an ADME property of a substance, as well as a corresponding computer program and computer system.